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Epigenetic Regulation of Embryonic Stem Cell Differeniation |
| Summary |
A major challenge in modern biology is to understand how “cell fate decisions” are regulated in stem and progenitor cells. These decisions govern whether a particular stem or progenitor cell differentiates into one type of cell or another. This question has major implications for regenerative medicine as well as our understanding of the molecular events that lead to cancer. It is becoming increasingly clear that, in addition to genetic alterations, cancer development involves the alteration of gene expression patterns as a result of 'epigenetic' changes (Feinberg et al., 2006). There are already several examples of epigenetic modifiers that are deregulated in cancer, e.g. BRD4 and EZH2 (Dawson and Kouzarides, 2012). The recent advent of “cancer epigenetic therapies”, such as those using BRD4 and EZH2 inhibitors to treat certain types of cancer, have demonstrated that knowledge in this field can lead to tangible successes in cancer treatment.
The Polycomb group proteins, which include EZH2, are centrally involved in cell fate decisions. Our central hypothesis is that the deregulation of the function of a set of Polycomb group proteins during cell fate decisions is central to tumour initiation. We are currently experimentally addressing this hypothesis, as well as investigating novel interactions between Polycomb group proteins and other chromatin regulators and DNA binding transcription factors involved in cell fate decisions. The goal is that this research will lead to breakthroughs in our understanding of stem cell biology as well as cancer. |
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Transcriptional Regulation of Cellular senescence |
| Summary |
Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening, or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. Central to cellular senescence are the p53 and pRb tumour suppressor pathways, which are activated upon cellular stress. We are studying the role of transcriptional regulators in the control of these cellular senescence pathways. Our goal is to harness this knowledge for future cancer therapies. |
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Brien GL, Gambero G, O'Connell DJ, Jerman E, Turner SA, Egan CM, Dunne EJ, Jurgens MC, Wynne K, Piao L, Lohan AJ, Ferguson N, Shi X, Sinha KM, Loftus BJ, Cagney G, Bracken AP, Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation, Nature Structural & Molecular Biology, 19, (12), 2012
Notes: [Nov 18. doi: 10.1038/nsmb.2449. ]
Url |
Lanigan F, Geraghty JG, Bracken AP., Transcriptional regulation of cellular senescence, Oncogene, 30, 2011, p2901–2911
Notes: [Pubmed ID: 21383691]
DOI |
Bracken AP, Helin K., Polycomb group proteins: navigators of lineage pathways led astray in cancer, Nature Reviews Cancer, 9, (11), 2009, p773 - 784
Notes: [Pubmed ID: 19851313]
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Bracken AP, Dietrich N, Pasini D, Hansen KH and Helin K, Genome-wide Mapping of Polycomb Target Genes Unravels Their Roles in Cell Fate Transitions., Genes and Development, 20, (9), 2006, p1123 - 1136
Notes: [PubMed ID: 16618801] TARA - Full Text
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Contact:helpdesk@tcd.ie
Last Updated:26-MAY-2013 |